OBJECTIVE: The mechanism of invasion of squamous cell carcinoma into normal tissue and basal laminae will be examined (1) at the leading edge of tumor in human head and neck biopsies; (2) in carcinoma in situ in biopsies and exfoliated cells and in early skin cancer of mice; and (3) in an isogeneic organ culture invasion model system consisting of cultured adult mouse epithelium and added dissociated cells from skin tumors induced in the same promotion. APPROACH: The biopsy material will be examined by thick-section stereoscopy using the Albany 1.2 MV High Voltage Electron Microscopy (HVEM) and light microscopic (LM) immunofluorescent staining of the tonofibril network. The kinetics of invasion in the model system will be quantitated in terms of the extent, depth and speed of invasion, invasive cell proliferation and dedifferentiation of the invasive cells. The extent of formation of the tonofibril network and its intracellular distribution will be examined by LM (Aniline Blue-Orange G-stain and immunofluorescence) and stereo HVEM both for motile-invaded cells and resting-invaded cells. Keratin synthesis will be modified by retinoids, protein synthesis inhibitors and hydrocortisone. The role of lysosomal enzyme release in invasion will be studied by stereo HVEM of acid phosphatase stained cells and by addition of proteases and protease inhibitors. The relation between invasion and cell proliferation will be studied by use of metabolic and microtubule inhibitors. At higher doses, chemotherapy agents will be used to search for selective toxicity for the invasive cells. It is hoped that this work will suggest new modes of therapy for squamous cell carcinomas.